This application is a competitive renewal of our previous Program Project Grant (PPG) entitled "Neonatal Anemia: Pathophysiology and Treatment." The renewal is based on hypotheses developed from findings of the original PPG plus new tissues arising in neonatal hematology and transfusion medicine. Although all objectives of the original PPG have been achieve with progress reported (512 manuscripts published, 7 submitted for review, and 15 in preparation), it is important to continue studies of neonatal anemia in a PPG setting because: 1) medical science has yet to achieve a comprehensive understanding of the physiology of neonatal erythropoiesis and the pathophysiology of the anemia of prematurity; and 2) severe, transfusion-dependent anemia continues to be a problem faced daily by preterm infants-for which the efficacy, toxicity and optimal use of therapies are not clearly defined. The theme of our PPG is to optimize management of neonatal anemia- particularly, severe anemia in preterm infants that requires red blood cell (RBC) transfusions. Two strategic goals and eight objectives will be met by three projects and a core. To optimize use of recombinant human erythropoietin (EPO) in treating neonatal anemia. Project #1 will continue to investigate the physiology, pharmacokinetics (PK) and pharmacodynamics (PD) of EPO-utilizing novel methods that employ biotinylated EPO. To investigate the role of iron (Fe) availability and protein nutrition in the pathophysiology of the anemia of prematurity and to define their requirements in treating and possibly preventing neonatal anemia, Project #2 will investigate the effect of protein and graded oral Fe intakes on erythropoiesis, the effects of RBC transfusions and EPO on Fe therapy, and the efficacy and safety of intravenous Fe therapy. To determine the benefits of autologous placental blood transfusions containing mature RBCs and hematopoietic/immunologic progenitor cells, Project #3 will study the effects of delayed umbilical cord clamping or the equivalent transfusions of placental blood on maintaining neonatal blood and RBC volumes and hematopoietic/immunological development. The Core will provide administrative, statistical and research support and biotinylation laboratory services to all projects. To accomplish these goals, additional investigators, with expertise in new areas, have been recruited to complement the ongoing efforts of our established PPG group.